Nanocarriers for protein and peptide delivery: Recent advances and progress

Abstract

Proteins and peptides have been recognized as potential leads for the synthesis of novel therapeutics to treat a variety of human ailments. Unfortunately, therapeutic potential and clinical applications of these biomacromolecules are challenging due to the verge of delivery applications. Nanocarriers offer unique potential to overcome various biological barriers and improve the delivery of therapeutic biomacromolecules like proteins and peptides. A smart nanocarriers-based drug delivery system can be defined as a system that has site-specific drug delivery in a controlled manner against all the physiological barriers and finally metabolized in the body. This review describes various nanocarriers investigated for the delivery of proteins and peptides to augment their clinical applications. Various biological aspects of protein and peptide delivery have been also focused. We also summarized various patents granted for nanocarrier reported to deliver these biomacromolecules followed by a landscape presentation of marketed nano-formulations for protein and peptide delivery.

Keywords

• Biomacromolecules
• nanocarriers
• protein delivery
• peptide delivery.

References

1. [1] Joseph M, Trinh HM, Mitra AK. Peptide and Protein-Based Therapeutic Agents. In Emerging Nanotechnologies for Diagnostics, Drug Delivery and Medical Devices. 2017; 146. [CrossRef]
2. [2] Cao SJ, Xu S, Wang HM, Ling Y, Dong J, Xia RD, Sun XH. Nanoparticles: oral delivery for protein and peptide drugs. AAPS PharmSciTech. 2019; 20(5): 190. [CrossRef]
3. [3] Global Peptide Therapeutics Market & Clinical Pipeline Insight 2026. Research and Markets. Available from: https://www.researchandmarkets.com/reports/4896465/global-peptide-therapeutics-market-and-clinical?utm_code=5c6d7v&utm_medium=GN . (Accessed on July 14, 2020).
4. [4] Patel A, Patel M, Yang X, K Mitra A. Recent advances in protein and peptide drug delivery: a special emphasis on polymeric nanoparticles. Protein Pept Lett. 2014; 21(11): 1102-1120. [CrossRef]
5. [5] Majumder J, Taratula O, Minko T. Nanocarrier-based systems for targeted and site specific therapeutic delivery. Adv Drug Deliv Rev. 2019; 144: 57-77. [CrossRef]
6. [6] Lee AC, Harris JL, Khanna KK, Hong JH. A comprehensive review on current advances in peptide drug development and design. Int J Mol Sci. 2019; 20(10): 1-21. [CrossRef]
7. [7] Tesauro D, Accardo A, Diaferia C, Milano V, Guillon J, Ronga L, Rossi F. Peptide-based drug-delivery systems in biotechnological applications: Recent advances and perspectives. Molecules. 2019; 24(2): 1-27. [CrossRef]
8. [8] Su C, Liu Y, Li R, Wu W, Fawcett JP, Gu J. Absorption, distribution, metabolism and excretion of the biomaterials used in Nanocarrier drug delivery systems. Adv Drug Deliv Rev. 2019; 143: 97-114. [CrossRef]

9. [9] Bayón-Cordero L, Alkorta I, Arana L. Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs. Nanomaterials. 2019; 9(3): 1-20. [CrossRef]
10. [10] Singh AP, Biswas A, Shukla A, Maiti P. Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles. Signal Transduct Target Ther. 2019; 4(33): 1-21. [CrossRef]
11. [11] Kompella UB, Lee VH. Delivery systems for penetration enhancement of peptide and protein drugs: design considerations. Adv Drug Deliv Rev. 2001; 46(1-3): 211-245. [CrossRef]
12. [12] Aguirre TA, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Deliv Rev. 2016; 106: 223-241.[CrossRef]
13. [13] Bruno BJ, Miller GD, Lim CS. Basics and recent advances in peptide and protein drug delivery. Ther Deliv. 2013;4(11):1443-67. [CrossRef]
14. [14] Awasthi R, Rathbone MJ, Hansbro PM, Bebawy M, Dua K. Therapeutic prospects of microRNAs in cancer treatment through nanotechnology. Drug Deliv Transl Res. 2018;8(1):97-110. [CrossRef]
15. [15] Cuggino JC, Blanco ER, Gugliotta LM, Igarzabal CI, Calderón M. Crossing biological barriers with nanogels to improve drug delivery performance. J Controll Rel. 2019;307:221-246. [CrossRef]
16. [16] Shaji J, Patole V. Protein and peptide drug delivery: oral approaches. Ind J Pharm Sci. 2008; 70(3): 269-277. [CrossRef]
17. [17] Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019; 11(3): 129. [CrossRef]
18. [18] Langguth P, Bohner V, Heizmann J, Merkle HP, Wolffram S, Amidon GL, Yamashita S. The challenge of proteolytic enzymes in intestinal peptide delivery. J Control Release. 1997; 46(1-2): 39-57. [CrossRef]
19. [19] Tulain UR, Ahmad M, Rashid A, Malik MZ, Iqbal FM. Fabrication of pH‐responsive hydrogel and its in vitro and in vivo evaluation. Adv Polym Tech. 2018;37(1):290-304. [CrossRef]
20. [20] Agarwal V, Khan MA. Current status of the oral delivery of insulin. Pharm Technol. 2001; 10: 76-90.
21. [21] Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci. 2007; 52(1): 1-7. [CrossRef]
22. [22] Bastian SE, Walton PE, Ballard FJ, Belford DA. Transport of IGF-I across epithelial cell monolayers. J Endocrinol. 1999; 162(3): 361-370. [CrossRef]
23. [23] De France KJ, Hoare T, Cranston ED. Review of hydrogels and aerogels containing nanocellulose. Chem Mater. 2017;29(11):4609-4631. [CrossRef]
24. [24] De France KJ, Chan KJ, Cranston ED, Hoare T. Enhanced mechanical properties in cellulose nanocrystal–poly (oligoethylene glycol methacrylate) injectable nanocomposite hydrogels through control of physical and chemical cross-linking. Biomacromolecules. 2016;17(2):649-660. [CrossRef]
25. [25] Kenngott EE, Cole S, Hein WR, Hoffmann U, Lauer U, Maass D, Moore L, Pfeil J, Rosanowski S, Shoemaker CB, Umair S. Identification of targeting peptides for mucosal delivery in sheep and mice. Mol Pharm. 2016; 13(1): 202-210. [CrossRef]
26. [26] Kang SK, Woo JH, Kim MK, Woo SS, Choi JH, Lee HG, Lee NK, Choi YJ. Identification of a peptide sequence that improves transport of macromolecules across the intestinal mucosal barrier targeting goblet cells. J Biotechnol. 2008; 135(2): 210-6. [CrossRef]
27. [27] Li, X.; Chen, D.; Le, C.; Zhu, C.; Gan, Y.; Hovgaard, L.; Yang, M. Novel mucus-penetrating liposomes as a potential oral drug delivery system: Preparation, in vitro characterization, and enhanced cellular uptake. Int J Nanomed. 2011; 6: 3151–3162. [CrossRef]
28. [28] Cu Y, Saltzman WM. Controlled surface modification with poly (ethylene) glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol Pharm. 2009; 6(1): 173-181. [CrossRef]
29. [29] Müller C, Leithner K, Hauptstein S, Hintzen F, Salvenmoser W, Bernkop-Schnürch A. Preparation and characterization of mucus-penetrating papain/poly (acrylic acid) nanoparticles for oral drug delivery applications. J Nanopart Res. 2013; 15(1): 1353. [CrossRef]
30. [30] Kamei N, Morishita M, Takayama K. Importance of intermolecular interaction on the improvement of intestinal therapeutic peptide/protein absorption using cell-penetrating peptides. J Control Release. 2009; 136(3): 179-86. [CrossRef]
31. [31] Reinholz J, Landfester K, Mailänder V. The challenges of oral drug delivery via nanocarriers. Drug Deliv. 2018; 25(1): 1694-1705. [CrossRef]
32. [32] Yang Y, Chen Q, Lin J, Cai Z, Liao G, Wang K, Bai L, Zhao P, Yu Z. Recent advance in polymer based microspheric systems for controlled protein and peptide delivery. Curr Med Chem. 2019; 26(13): 2285-2296. [CrossRef]
33. [33] Ma YQ. Theoretical and computational studies of dendrimers as delivery vectors. Chem Soc Rev. 2013; 42(2): 705- 727. [CrossRef]
34. [34] Guixer B, Arroyo X, Belda I, Sabidó E, Teixidó M, Giralt E. Chemically synthesized peptide libraries as a new source of BBB shuttles. Use of mass spectrometry for peptide identification. J Pept Sci. 2016; 22(9): 577-591. [CrossRef]
35. [35] Li Y, Zheng X, Gong M, Zhang J. Delivery of a peptide-drug conjugate targeting the blood brain barrier improved the efficacy of paclitaxel against glioma. Oncotarget. 2016; 7(48): 79401-79407. [CrossRef]
36. [36] Moscariello P, Ng DY, Jansen M, Weil T, Luhmann HJ, Hedrich J. Brain delivery of multifunctional dendrimer protein bioconjugates. Adv Sci. 2018; 5(5): 1700897. [CrossRef]
37. [37] Yamashita S, Katsumi H, Hibino N, Isobe Y, Yagi Y, Kusamori K, Sakane T, Yamamoto A. Development of PEGylated carboxylic acid-modified polyamidoamine dendrimers as bone-targeting carriers for the treatment of bone diseases. J Control Release. 2017; 262: 10-17. [CrossRef]
38. [38] Tunki L, Kulhari H, Sistla R, Pooja D. Dendrimer-based targeted drug delivery. Pharmaceutical Applications of Dendrimers. 2020: 107–129. [CrossRef]
39. [39] Araújo RV, Santos SD, Igne Ferreira E, Giarolla J. New advances in general biomedical applications of PAMAM dendrimers. Molecules. 2018; 23(11): 2849. [CrossRef]
40. [40] Hill E, Shukla R, Park SS, Baker Jr JR. Synthetic PAMAM–RGD conjugates target and bind to odontoblast-like MDPC 23 cells and the predentin in tooth organ cultures. Bioconjugate Chem. 2007;18(6):1756-62. [CrossRef]
41. [41] Kaneda Y. Virosomes: evolution of the liposome as a targeted drug delivery system. Adv Drug Deliv Reviews. 2000; 43(2-3): 197-205. [CrossRef]
42. [42] Dai C, Wang B, Zhao H, Li B, Wang J. Preparation and characterization of liposomes-in-alginate (LIA) for protein delivery system. Colloids Surf B: Biointerfaces. 2006; 47(2): 205-210. [CrossRef]
43. [43] Yang J, Bahreman A, Daudey G, Bussmann J, Olsthoorn RC, Kros A. Drug delivery via cell membrane fusion using lipopeptide modified liposomes. ACS Cent Sci. 2016; 2(9): 621-30. [CrossRef]
44. [44] Torchilin VP, Rammohan R, Weissig V, Levchenko TS. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. PNAS. 2001; 98(15): 8786-8791. [CrossRef]
45. [45] Ganesan P, Ramalingam P, Karthivashan G, Ko YT, Choi DK. Recent developments in solid lipid nanoparticle and surface-modified solid lipid nanoparticle delivery systems for oral delivery of phyto-bioactive compounds in various chronic diseases. Int J Nanomed. 2018; 13: 1569-1583. [CrossRef]
46. [46] Martins S, Sarmento B, Ferreira DC, Souto EB. Lipid-based colloidal carriers for peptide and protein delivery-liposomes versus lipid nanoparticles. Int J Nanomed. 2007; 2(4): 595-607.
47. [47] Zhang N, Ping Q, Huang G, Xu W, Cheng Y, Han X. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin. Int J Pharm. 2006; 327(1-2): 153-159. [CrossRef]
48. [48] Mishra V, Bansal KK, Verma A, Yadav N, Thakur S, Sudhakar K, Rosenholm JM. Solid lipid nanoparticles: Emerging colloidal nano drug delivery systems. Pharmaceutics. 2018; 10(4): 1-21. [CrossRef]
49. [49] Tekade RK, Maheshwari R, Tekade M, Chougule MB. Solid lipid nanoparticles for targeting and delivery of drugs and genes. In: Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. 2017: 256-286. [CrossRef]
50. [50] Almeida AJ, Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Deliv Rev. 2007; 59(6): 478-490. [CrossRef]
51. [51] Moritz M, Geszke-Moritz M. Recent developments in the application of polymeric nanoparticles as drug carriers. Adv Clin Exp Med. 2015; 24(5): 749-58. [CrossRef]
52. [52] Bennet D, Kim S. Polymer nanoparticles for smart drug delivery. Sezer AD (Editor). In: Application of Nanotechnology in Drug Delivery. 2014: 257-310. [CrossRef]
53. [53] Lou B, De Beuckelaer A, Boonstra E, Li D, De Geest BG, De Koker S, Mastrobattista E, Hennink WE. Modular core-shell polymeric nanoparticles mimicking viral structures for vaccination. J Control Release. 2019; 293: 48-62. [CrossRef]
54. [54] Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B: Biointerfaces. 2010; 75(1): 1-18. [CrossRef]
55. [55] Ye Y, Yu J, Wen D, Kahkoska AR, Gu Z. Polymeric microneedles for transdermal protein delivery. Adv Drug Deliv Rev. 2018; 127: 106-118. [CrossRef]
56. [56] Lee KY, Yuk SH. Polymeric protein delivery systems. Prog Polym Sci. 2007; 32(7): 669-697. [CrossRef]
57. [57] Castellanos IJ, Crespo R, Griebenow K. Poly (ethylene glycol) as stabilizer and emulsifying agent: a novel stabilization approach preventing aggregation and inactivation of proteins upon encapsulation in bioerodible polyester microspheres. J Control Release. 2003; 88(1): 135-145. [CrossRef]
58. [58] Li JK, Wang N, Wu XS. Poly (vinyl alcohol) nanoparticles prepared by freezing–thawing process for protein/peptide drug delivery. J Control Release. 1998; 56(1-3): 117-126. [CrossRef]
59. [59] Xu W, Ling P, Zhang T. Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. J Drug Deliv. 2013; 2013: 340315. [CrossRef]
60. [60] Awasthi R, Bhushan B, Kulkarni GT. Concepts of nanotechnology in nanomedicine: From discovery to applications. In: Targeting Chronic Inflammatory Lung Diseases Using Advanced Drug Delivery Systems. Dua K, Hansbro P, Wadhwa R, Haghi M, Pont L, Williams K, Ed.; Elsevier Science B. V: Amsterdam, 2020; Vol. 1. [CrossRef]
61. [61] Ahmad Z, Shah A, Siddiq M, Kraatz HB. Polymeric micelles as drug delivery vehicles. RSC Adv. 2014; 4(33): 17028-38. [CrossRef]
62. [62] Demeule M, Regina A, Che C, Poirier J, Nguyen T, Gabathuler R, Castaigne JP, Beliveau R. Identification and design of peptides as a new drug delivery system for the brain. J Pharmacol Exp Ther. 2008; 324(3): 1064-1072. [CrossRef]
63. [63] Batrakova EV, Bronich TK, Vetro JA, Kabanov AV. Polymer micelles as drug carrier. In: Torchilin VP (editor). Nanoparticulates as Drug Carriers. Imperial College Press, London. 2006; pp. 57-94.
64. [64] Kwon GS, Kataoka K. Block copolymer micelles as long-circulating drug vehicles. Adv Drug Deliv Rev. 1995; 16(2-3): 295-309. [CrossRef]
65. [65] Medeiros-Neves B, Nemitz MC, Silveira Fachel FN, Teixeira HF. Recent patents concerning the use of nanotechnology-based delivery systems as skin penetration enhancers. Recent Pat Drug Deliv Formul. 2019; 13(3):192-202. [CrossRef]
66. [66] Livney YD. Potato protein nanoparticles. United States Patent US20160220502A1. August 4, 2016.
67. [67] Aimi M, Nemori R, Miyashita Y, Yokoyama H. Enzymatically crosslinked protein nanoparticles. WO2007086613A1. August 2, 2007.
68. [68] Rotello VM, Mout R, Nanoparticle-protein complex for intracellular protein delivery. United States Patent US 15/547,404. January 25, 2018.
69. [69] Jianwu Z, Da L, Pingfan R. Paclitaxel-loaded semen armeniacae amarae protein nanocarrier and preparation method thereof. CN109956995. July 02, 2019.
70. [70] Wonjae Lee, Ha Ho-Kyung, Jinwook Kim, Seung Minkim, Kyoung Sikhan. Hydrogel nano carrier derived from goat milk protein resolvent and manufacturing method thereof. KR1018250290000*. March 14, 2018
71. [71] Kun H. Zein/protein-polysaccharide electrostatic complex core/shell type nanocarrier as well as preparation method and application thereof. CN106692978A. February 14, 2020.
72. [72] Bookbinder L. Targeted prdm gene or protein modulation therapeutic agents. WO2011050178A3. September 22, 2011.
73. [73] Ventola CL. Progress in nanomedicine: approved and investigational nanodrugs. Pharmacy and Therapeutics. 2017; 42(12): 742-755.
74. [74] Zhong H, Chan G, Hu Y, Hu H, Ouyang D. A comprehensive map of FDA-approved pharmaceutical products. Pharmaceutics. 2018; 10(4): 1-19. [CrossRef]
75. [75] Yun Y, Cho YW, Park K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv Drug Deliv Rev. 2013; 65(6): 822-32. [CrossRef]
76. [76] Pisal DS, Kosloski MP, Balu-Iyer SV. Delivery of therapeutic proteins. J Pharm Sci. 2010; 99(6): 2557-2575. [CrossRef]
77. [77] Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015; 20(1): 122-128. [CrossRef]
78. [78] Niu Z, Conejos-Sánchez I, Griffin BT, O’Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Adv Drug Deliv Rev. 2016; 106: 337-354. [CrossRef]
79. [79] Ma B, Niu F, Qu X, He W, Feng C, Wang S, Ouyang Z, Yan J, Wen Y, Xu D, Shao Y. A tetrameric protein scaffold as a nano-carrier of antitumor peptides for cancer therapy. Biomaterials. 2019; 1-12. [CrossRef]
80. [80] Baker ME. Albumin's role in steroid hormone action and the origins of vertebrates: is albumin an essential protein? FEBS Lett. 1998; 439: 9–12. [CrossRef]
81. [81] Debelle L, Tamburro AM. Elastin: molecular description and function. Int J Biochem Cell Biol. 1999; 31: 261–272. [CrossRef]
82. [82] Gupta AK, Berry CC, Gupta M, Curtis A. Receptor-mediated targeting of magnetic nanoparticles using insulin as a surface ligand to prevent endocytosis, IEEE Trans. Nanobioscience. 2003; 2: 255–261. [CrossRef]
83. [83] Mo Y, Lim LY. Paclitaxel-loaded PLGA nanoparticles: potentiation of anticancer activity by surface conjugation with wheat germ agglutinin. J Control Release. 2005; 108(2-3): 244-262. [CrossRef]
84. [84] Gref R, Couvreur P, Barratt G, Mysiakine E. Surface-engineered nanoparticles for multiple ligand coupling. Biomaterials. 2003; 24(24): 4529-4537. [CrossRef]
85. [85] Gao X, Wang T, Wu B, Chen J, Chen J, Yue Y, Dai N, Chen H, Jiang X. Quantum dots for tracking cellular transport of lectin-functionalized nanoparticles. Biochem Biophys Res Commun. 2008; 377(1): 35-40. [CrossRef]
86. [86] Weissenböck A, Wirth M, Gabor F. WGA-grafted PLGA-nanospheres: preparation and association with Caco-2 single cells. J Control Rel. 2004; 99(3): 383-392. [CrossRef]
87. [87] Mo Y, Lim LY. Preparation and in vitro anticancer activity of wheat germ agglutinin (WGA)-conjugated PLGA nanoparticles loaded with paclitaxel and isopropyl myristate. J Control Rel. 2005; 107(1): 30-42. [CrossRef]
88. [88] Yin Y, Chen D, Qiao M, Wei X, Hu H. Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution. J Control Rel. 2007; 123(1): 27-38. [CrossRef]
89. [89] Jeong YI, Seo SJ, Park IK, Lee HC, Kang IC, Akaike T, Cho CS. Cellular recognition of paclitaxel-loaded polymeric nanoparticles composed of poly (γ-benzyl L-glutamate) and poly (ethylene glycol) diblock copolymer endcapped with galactose moiety. Int J Pharm. 2005; 296(1-2): 151-161. [CrossRef]
90. [90] Bellis SL. Advantages of RGD peptides for directing cell association with biomaterials. Biomaterials. 2011; 32(18): 4205-4210. [CrossRef]
91. [91] Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996; 12(1): 697-715. [CrossRef]
92. [92] Hersel U, Dahmen C, Kessler H. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials. 2003; 24(24): 4385-4415. [CrossRef]
93. [93] Andersson M, Fromell K, Gullberg E, Artursson P, Caldwell KD. Characterization of surface-modified nanoparticles for in vivo biointeraction. A sedimentation field flow fractionation study. Anal Chem. 2005; 77(17): 5488-5493. [CrossRef]
94. [94] Montet X, Funovics M, Montet-Abou K, Weissleder R, Josephson L. Multivalent effects of RGD peptides obtained by nanoparticle display. J Med Chem. 2006; 49(20): 6087-6093. [CrossRef]
95. [95] Qian ZM, Li H, Sun H, Ho K. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev. 2002; 54(4): 561-587. [CrossRef]
96. [96] Wagner E, Curiel D, Cotten M. Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv Drug Deliv Rev. 1994; 14(1): 113-135. [CrossRef]
97. [97] Daniels TR, Delgado T, Helguera G, Penichet ML. The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin Immunol. 2006; 121(2): 159-176. [CrossRef]
98. [98] Berry CC, Charles S, Wells S, Dalby MJ, Curtis AS. The influence of transferrin stabilised magnetic nanoparticles on human dermal fibroblasts in culture. Int J Pharm. 2004; 269(1): 211-25. [CrossRef]
99. [99] Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML. The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol. 2006; 121(2): 144-158. [CrossRef]
100. [100] Franks SJ, Firipis K, Ferreira R, Hannan KM, Williams RJ, Hannan RD, Nisbet DR. Harnessing the self-assembly of peptides for the targeted delivery of anti-cancer agents. Mater Horiz. 2020; 7: 1996-2010. [CrossRef]
101. [101] Qin Y, Qin ZD, Chen J, Cai CG, Li L, Feng LY, Wang Z, Duns GJ, He NY, Chen ZS, Luo XF. From antimicrobial to anticancer peptides: the transformation of peptides. Recent Pat Anticancer Drug Discov. 2019; 14(1): 70-84. [CrossRef]
102. [102] Battaglia L, Ugazio E. Lipid nano-and microparticles: an overview of patent-related research. J Nanomater. 2019; 2019. [CrossRef]